Hippo Signaling Is Essential for the Maintenance of Zona Glomerulosa Cell Fate in the Murine Adrenal Cortex

Cells of the zona glomerulosa (zG), the outermost zone of the adrenal cortex, secrete aldosterone and transdifferentiate into glucocorticoid-producing cells of the zona fasciculata (zF) during adrenal homeostasis. However, our understanding of the signaling pathways mediating zG cell maintenance or their transdifferentiation into zF cells is incomplete. Hippo is a major pathway that regulates cell proliferation/differentiation during embryogenesis and postnatal tissue homeostasis. Hypothesizing that Hippo signaling could be involved in zG cell maintenance or transdifferentiation, we generated a mouse model in which the two main kinases of the Hippo signaling cascade large tumor suppressor homolog kinases 1/2 (Lats1 and Lats2) are specifically inactivated in zG cells. Here we show that loss of function of Lats1 and Lats2 impairs zG steroidogenesis and leads to zG cell transdifferentiation into cells sharing characteristics with chondroblasts/osteoblasts rather than zF cells. Furthermore, we demonstrate that this phenotype can be rescued by the concomitant inactivation of the transcriptional coactivators Yes-associated protein (Yap) and transcriptional coactivator with PDZ-binding motif (Taz) with Lats1 and Lats2. Finally, we show that expression of a constitutively active form of YAP (YAP5SA) in zG cells does not alter their fate as severely as the loss of Lats1 and Lats2 but leads to adrenal hyperplasia. Together, these findings highlight the critical role of Hippo signaling in maintaining zG cell fate and function and provide key insights into broader mechanisms underlying cellular differentiation.